NM_000517.6:c.384G>C

Variant names:

• chr16-173555-G-C
• rs33972894
• NM_000517.6:c.384G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000517.6(HBA2):​c.384G>C​(p.Lys128Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HBA2 NM_000517.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44

Genes affected

HBA2 (HGNC:4824): (hemoglobin subunit alpha 2) The human alpha globin gene cluster located on chromosome 16 spans about 30 kb and includes seven loci: 5'- zeta - pseudozeta - mu - pseudoalpha-1 - alpha-2 - alpha-1 - theta - 3'. The alpha-2 (HBA2) and alpha-1 (HBA1) coding sequences are identical. These genes differ slightly over the 5' untranslated regions and the introns, but they differ significantly over the 3' untranslated regions. Two alpha chains plus two beta chains constitute HbA, which in normal adult life comprises about 97% of the total hemoglobin; alpha chains combine with delta chains to constitute HbA-2, which with HbF (fetal hemoglobin) makes up the remaining 3% of adult hemoglobin. Alpha thalassemias result from deletions of each of the alpha genes as well as deletions of both HBA2 and HBA1; some nondeletion alpha thalassemias have also been reported. [provided by RefSeq, Jul 2008]

ENSG00000290038 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HBA2	NM_000517.6	c.384G>C	p.Lys128Asn	missense_variant	Exon 3 of 3	ENST00000251595.11	NP_000508.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HBA2	ENST00000251595.11	c.384G>C	p.Lys128Asn	missense_variant	Exon 3 of 3	1	NM_000517.6	ENSP00000251595.6

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459104 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.98	D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.6	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.72
MutPred		0.77		Loss of methylation at K128 (P = 0.0042);.;
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs33972894; hg19: chr16-223554;